2019 Fiscal Year Final Research Report

Introduction of precision medicine in renal transplantation: attempt to overcome HLA mismatch by TCR/BCR control

Research Project

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Project/Area Number	18K19593
Research Category	Grant-in-Aid for Challenging Research (Exploratory)
Allocation Type	Multi-year Fund
Review Section	Medium-sized Section 55:Surgery of the organs maintaining homeostasis and related fields
Research Institution	Aichi Medical University
Principal Investigator	Kobayashi Takaaki 愛知医科大学, 医学部, 教授 (70314010)
Co-Investigator(Kenkyū-buntansha)	岩崎研太愛知医科大学, 医学部, 准教授 (10508881) 三輪祐子愛知医科大学, 医学部, 助教 (90572941)
Project Period (FY)	2018-06-29 – 2020-03-31
Keywords	移植・再生医療 / 抗体関連型拒絶反応 / Ｔ細胞受容体 / ドナー特異的ＨLA抗体 / レパトア解析 / 個別化医療
Outline of Final Research Achievements	HLA mismatches cannot be avoided in kidney transplantation. To control chronic antibody-mediated rejection (ABMR) caused by donor specific HLA antibody (DSA) after kidney transplantation, our attention has been directed towards T cell receptor (TCR) and B cell receptor (BCR). Analysis of PBMC mRNA from recipients with de novo DSA showed the specific trend in TCR beta, but not in TCR alpha or BCR. Candidates for TCR beta which might be involved in de novo DSA production have been identified. In vitro assay which can analyze indirect recognition pathway of CD4+ T cells was developed. We detected human CD45+ cells and IgG (IgM) in blood circulation using humanized (NSG) mice model. In silico analysis of T cell epitopes for over 700 renal transplant recipients revealed usefulness in de novo DSA risk prediction. To develop early diagnosis and effective avoidance of chronic ABMR, theoretical rationale and feasibility of TCR-targeted research have been demonstrated.
Free Research Field	移植外科、移植免疫
Academic Significance and Societal Importance of the Research Achievements	わが国では慢性腎臓病の患者数は1300万人以上と推定され、年間４万人以上が末期腎不全となり、血液透析、腹膜透析、腎移植の腎代替療法を受けている。腎移植は末期腎不全に対する最良の治療とされているが、腎代替療法の中でわずか2-3％程度であり、ドナー不足問題とともに長期成績のさらなる改善が課題となっている。本研究では、次世代シークセンスなどの最新技術を用い、免疫応答の第一歩であるT細胞受容体に着目し、１兆種類以上ある多様性から関連のある受容体を特定することができた。慢性拒絶反応に関わるドナーHLAに対する抗体産生を予防し、効率的に回避するための研究アプローチの妥当性を明らかにした。